JP6943560B2 - Method for Producing 2-Amino-6-Methylnicotinic Acid Ester or Protonate thereof - Google Patents

Description

The present invention relates to a method for producing 2-amino-6-methylnicotinic acid ester or a protonate thereof. Specifically, the present invention provides a high-yield, easy-to-implement, inexpensive 2-amino-6-methylnicotinic acid ester, which is an intermediate compound for producing a compound useful as an active ingredient of a pharmaceutical or agricultural chemical. Regarding the method of manufacturing.

Pharmaceuticals or pesticides produced using 2-amino-6-methylnicotinic acid ester or 2-amino-6-methylnicotinic acid obtained by hydrolyzing it as an intermediate are described, for example, in WO 2005/33079. It is described in JP-A-2010-083861 and WO2014 / 6945.
Examples of the method for producing 2-amino-6-methylnicotinic acid ester include a method of reacting a hydrochloride salt of amidinoacetic acid with a sodium formylacetone salt (Patent Document 1), and a method of malonic acid-ethyl ester-iminoethyl ether. A method of reacting a hydrochloride with 3-oxobutyl aldehyde (Non-Patent Document 1), and a method of reacting ethyl 3,3-diaminoacrylate with 1-amino-1-buten-3-one (Non-Patent Document 2). ) Etc. are known.

Special Publication No. 45-40288

Chemische Berichte, Vol. 73, 544, p. 545 (1940) Journal of Heterocyclic Chemistry, Vol. 33, No. 6, p. 1817 (1996)

However, in the production method of Patent Document 1, since the sodium formylacetone salt is used, the reaction proceeds under basic conditions, and the yield of 2-amino-6-methylnicotinic acid ester is 56%, which is sufficient. The yield is not high.
Further, in the method disclosed in Non-Patent Document 1, the yield is as low as 10%.
Further, although the method disclosed in Non-Patent Document 2 does not particularly describe the yield, it is difficult to obtain the raw material 1-amino-1-butene-3-one itself, and the production method tends to be expensive.
Therefore, a method for producing 2-amino-6-methylnicotinic acid ester or a protonate thereof, which has a high yield and is easy to implement, has been strongly desired.

As a result of diligent studies to solve the above problems, the present inventors have found that the above problems can be solved by the following methods, and have arrived at the present invention.
That is, in the present invention, the following equation (1),

（式（１）中、Ｒは、アリール基または炭素数１〜８のアルキル基を示し、該アリール基またはアルキル基は、置換基を有していてもよい）で表される２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法であって、
極性有機溶媒中、下式（２）、

(In the formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, and the aryl group or the alkyl group may have a substituent) 2-amino-. A method for producing a 6-methylnicotinic acid ester or a protonate thereof.
In a polar organic solvent, the following formula (2),

（式（２）中、Ｒは、上記定義の通りであり、ＨＸは、プロトン酸を示し、ｎは、１〜３の整数を示す。）で表されるアルコキシカルボニルメチルカルボアミジン・プロトン酸塩と、３−オキソブチルアルデヒドまたはそのアセタール類の少なくともいずれかを、実質的に塩基性物質の非存在下で反応させることを特徴とする２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法に関するものである。
本発明においては、上記反応後、反応液から極性有機溶媒および低沸点成分を蒸留で除去する濃縮工程と、上記濃縮工程によって得られた濃縮液から上記式（１）の化合物のプロトン酸塩を水層に抽出する抽出工程と、上記抽出工程によって得られた抽出水層にアルカリ化合物を加えて結晶を析出させる晶析工程と、を含むことが好ましい。

(In the formula (2), R is as defined above, HX is a protonic acid, and n is an integer of 1 to 3). And 2-amino-6-methylnicotinic acid ester or a protonate thereof, which comprises reacting at least one of 3-oxobutylaldehyde or its acetals in the absence of substantially a basic substance. It is related to the manufacturing method of.
In the present invention, after the above reaction, a concentration step of removing the polar organic solvent and low boiling point components from the reaction solution by distillation, and a protonate of the compound of the above formula (1) are extracted from the concentrate obtained by the above concentration step. It is preferable to include an extraction step of extracting into an aqueous layer and a crystallization step of adding an alkaline compound to the extraction aqueous layer obtained by the above extraction step to precipitate crystals.

According to the present invention, 2-amino-6-methylnicotinic acid ester, which is an intermediate compound for producing a compound useful as an active ingredient of a medicine or agrochemical, or a protonate thereof can be easily implemented in a high yield. And can be manufactured at low cost.

Hereinafter, the present invention will be described in more detail.
In the present invention, the following equation (1),

（式（１）中、Ｒは、アリール基または炭素数１〜８のアルキル基を示し、該アリール基またはアルキル基は置換基を有していてもよい。）で表される２−アミノ−６−メチルニコチン酸エステル又はそのプロトン酸塩の製造方法であって、
極性有機溶媒中、下式（２）、

(In the formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, and the aryl group or the alkyl group may have a substituent). A method for producing a 6-methylnicotinic acid ester or a protonate thereof.
In a polar organic solvent, the following formula (2),

（式（２）中、Ｒは、上記定義の通りであり、ＨＸは、プロトン酸を示し、ｎは、１〜３の整数を示す。）で表されるアルコキシカルボニルメチルカルボアミジン・プロトン酸塩と、３−オキソブチルアルデヒドまたはそのアセタール類の少なくともいずれかを、実質的に塩基性物質の非存在下で反応させる方法に関するものである。

(In the formula (2), R is as defined above, HX is a protonic acid, and n is an integer of 1 to 3). And at least one of 3-oxobutylaldehyde or its acetals, the present invention relates to a method for reacting with substantially the absence of a basic substance.

In the above formulas (1) and (2), the aryl group represented by R is not particularly limited, and examples thereof include a phenyl group and a trill group, and the number of carbon atoms represented by R is 1 to 1. The alkyl group of 8 is not particularly limited, but for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. , Pentyl group, hexyl group, heptyl group, octyl group and the like.
The substituent in the aryl group or the alkyl group is not particularly limited, and examples thereof include an alkoxy group and a cyano group.
The protonate of the above formula (1) is not particularly limited, but for example, hydrogen chloride salt, hydrogen bromide salt, sulfate, phosphate, methane sulfonate, benzene sulfonate, and the like. Examples thereof include formates, acetates and oxalates. The protonic acid as HX in the formula (2) means a protonic acid involved in the formation of the protonate of the above formula (1).

The alkoxycarbonylmethylcarboamidine protonate represented by the above formula (2) used in the production method of the present invention is, for example, from a known compound according to the method described in International Publication No. 2008/33745. It can be synthesized immediately.
The 3-oxobutyraldehyde or acetals thereof used in the production method of the present invention can be immediately synthesized from a known compound according to, for example, the method described in JP-A-6-16591.

[Reaction process]
In one aspect of the production method of the present invention, the alkoxycarbonylmethylcarboamidine protonate represented by the above formula (2) is added to a polar organic solvent, and 3-oxobutyraldehyde or its acetals are further added. , Heat and stir.
Each compound in the reaction step will be described in more detail below.
(Alkoxycarbonylmethylcarboamidine / protonate)
The aryl group represented by R in the above formula (2) of the alkoxycarbonylmethyl carboamidine protonate is not particularly limited, and examples thereof include a phenyl group and a trill group. The alkyl group having 1 to 8 carbon atoms represented by (1) is not particularly limited, but is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or sec-. Butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group and the like can be mentioned, and the sulfonic acid represented by HX is not particularly limited, but for example, hydrogen chloride or bromide. Examples thereof include hydrogen, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid and oxalic acid.

(3-oxobutyraldehyde or its acetals)
3-oxobutyraldehyde or its acetals are not particularly limited, but are, for example, 3-oxobutyraldehyde, 1-methoxy-1-butanol-3-one, 1-ethoxy-1-butanol-3. -On, 1,1-dimethoxy-3-butanone, 1,1-diethoxy-3-butanone, 2,4,4-trimethoxy-2-butanol, 2,4,4-triethoxy-2-butanol, 1,1 , 3,3-Tetramethoxybutane, 1,1,3,3-tetraethoxybutane, 1,1,3-trimethoxy-2-butane, 1,1,3-triethoxy-2-butane and the like. The acetals also include hemiacetals located between aldehydes and acetals. Examples of the hemiacetal include 1-methoxy-1-butanol-3-one and 1-ethoxy-1-butanol-3-one.

(Polar organic solvent)
The polar organic solvent is not particularly limited, but is, for example, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidi. Examples thereof include alcohols such as non-, dimethylsulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and tert-butanol.

(Reaction condition)
The compound of the above formula (2) is preferably in the range of 5 to 50% by mass in the polar organic solvent. The amount of 3-oxobutylaldehyde or acetals thereof used is preferably in the range of 0.8-fold to 3.0-fold molars with respect to the compound of the above formula (2), and 1.0-fold molars. More preferably, it is in the range of ~ 2.0 times the molar amount. This makes it possible to react efficiently.
The reaction step may be carried out in an atmosphere of an inert gas such as nitrogen or argon, or a polar organic solvent dehydrated with a molecular sieve or the like may be used.
The temperature inside the reactor in the reaction step is preferably in the range of 30 to 200 ° C., and more preferably in the range of 50 to 150 ° C. from the viewpoint of reaction efficiency.

The reaction step is preferably carried out in the absence of a substantially basic substance. "Substantially in the absence of a basic substance" may be in the presence of a basic substance within a range that does not significantly reduce the reaction yield. Preferably, no basic material is present. When the reaction is carried out by adding a base such as potassium carbonate or sodium methoxide, the reaction rate is lowered and the selectivity of the target product is also lowered. Further, the reaction substrate is also preferably non-basic. When the reaction is carried out using a free form of ethoxycarbonylmethylcarboamidine, the reaction rate is lowered and the selectivity of the target product is also lowered, which is outside the scope of the present invention. When the reaction is carried out in the absence of a basic substance using a non-basic reaction substrate, the desired product can be obtained in high yield.

[Processing after reaction]
In one aspect of the production method of the present invention, after the reaction, a concentration step of removing the polar organic solvent and the low boiling point component from the reaction solution by distillation, and the concentration solution obtained by the above concentration step are used to obtain the compound of the above formula (1). It is preferable to include an extraction step of extracting the protonate into an aqueous layer and a crystallization step of adding an alkaline compound to the extraction aqueous layer obtained by the above extraction step to precipitate crystals.
According to the above configuration, 2-amino-6-methylnicotinic acid ester can be easily taken out in high yield.
Further, following the crystallization step, a solid-liquid separation step of separating the slurry obtained by the crystallization step into a solid and a liquid, and a drying step of drying the wet crystal obtained by the solid-liquid separation step are performed. It is more preferable to include it.

(Concentration process)
The concentration step is to concentrate by removing the polar organic solvent and the low boiling point component from the reaction solution by distillation. Distillation may be carried out under normal pressure or under reduced pressure. The degree of decompression and the distillation temperature are appropriately set depending on the type of polar organic solvent. Polar organic solvents and low boiling components are preferably removed as much as possible.

(Extraction process)
In the extraction step, water and an organic solvent are added to the concentrate obtained by the above concentration step, the protonate of the compound of the above formula (1) is extracted into an aqueous layer, and the aqueous layer and the organic layer are separated by liquid separation. do. In the extraction step, it is preferable to further add mineral acid in order to improve the extraction efficiency.
Water or an aqueous solution of mineral acid may be added to the separated organic layer, and the extraction step may be performed again.
The amount of water used in the extraction step is, for example, preferably 0.1 to 10 times the volume of the concentrated solution, and more preferably 0.5 to 5 times the volume.
The amount of the organic solvent used in the extraction step is, for example, preferably 0.1 to 10 times the volume of the concentrated solution, and more preferably 0.5 to 5 times the volume.
The amount of the mineral acid used in the extraction step is preferably 2 times mol or less, more preferably 1 time mol or less, based on the compound of the above formula (2) used in the reaction.

The organic solvent used in the extraction step is not particularly limited, and examples thereof include an ester solvent, an ether solvent, and a halogenated hydrocarbon solvent. Examples of the ester solvent include n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and tert-butyl acetate. Examples of the ether solvent include ethyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether and the like. Examples of the halogenated hydrocarbon solvent include methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chlorobenzene and the like.

The mineral acid used in the extraction step is not limited to these, and examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, and benzenesulfonic acid.
In another aspect of the extraction step, water is added to the concentrate obtained by the above concentration step, the protonate of the compound of the above formula (1) is extracted into an aqueous layer, and separated into an aqueous layer and precipitated crystals by filtration. .. In the extraction step, it is preferable to further add mineral acid in order to improve the extraction efficiency.
The amount of water used in another aspect of the extraction step is, for example, preferably 0.1 to 10 times the volume of the concentrated solution, and more preferably 0.5 to 5 times the volume.
The amount of the mineral acid used in another aspect of the extraction step is preferably 2 times mol or less, more preferably 1 time mol or less, based on the compound of the above formula (2) used in the reaction.
Mineral acids used in another aspect of the extraction step include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and the like. ..

(Crystalization process)
In the crystallization step, an alkaline compound is added to the extraction aqueous layer obtained by the above extraction step to precipitate crystals. The alkaline compound may be added as a solid or as an aqueous solution of 1% by mass or more.
The amount of the alkaline compound used in the crystallization step is preferably 5 times mol or less, more preferably 3 times mol or less, based on the compound of the above formula (2) used in the reaction.
The alkaline compound used in the crystallization step is not limited to these, for example, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, carbonic acid. Calcium, ammonia and the like can be mentioned.

(Solid-liquid separation process)
In the solid-liquid separation step, the slurry obtained by the crystallization step is separated into a solid and a liquid by a method such as filtration. The solid may be washed with water to remove the alkaline compounds remaining on the solid.

(Drying process)
In the drying step, the wet crystals obtained by the solid-liquid separation step are dried by a method such as an evaporator, shelf drying, or a spray dryer. Drying may be carried out under normal pressure or under reduced pressure. The degree of decompression or the drying temperature is appropriately set.
The reaction time of the 2-amino-6-methylnicotinic acid ester or its protonate and the alkoxycarbonylmethyl carboamidine protonate is, for example, 5 hours or more, preferably 10 hours or more. A constant yield can be achieved, especially regardless of time.
Examples are shown below, and embodiments of the present invention will be described in more detail. Of course, the present invention is not limited to the following examples, and it goes without saying that various aspects can be used for details. Furthermore, the present invention is not limited to the above-described embodiment, and various modifications can be made within the scope of the claims, and the present invention also relates to an embodiment obtained by appropriately combining the disclosed technical means. It is included in the technical scope of the invention. In addition, all the documents described in the present specification are incorporated by reference.

[Purity measurement method]
The purity of 2-amino-6-methylnicotinic acid ester was measured by the internal standard method of gas chromatography.

[Example 1]
8.33 g (0.05 mol) of ethoxycarbonylmethylcarboamidine hydrochloride and 7.4 ml (0.05 mol) of 1,1-dimethoxy-3-butanone were heated and stirred under reflux with 100 ml of acetonitrile for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure at 4 kPa. To the residue was added 30 g of water, 30 g of ethyl acetate and 2.5 g (0.025 mol) of 37% hydrochloric acid, and the aqueous layer was separated after stirring. The aqueous layer was slowly added to 88.8 g (0.10 mol) of a 15.5% aqueous potassium carbonate solution. The precipitated crystals were filtered and washed twice with 50 g of water. The wet crystals were dried at 60 ° C. under a reduced pressure of 4 kPa to obtain 6.35 g of light brown crystals (equivalent to a yield of 70.5%). The purity of ethyl 2-amino-6-methylnicotinate in the dried product was 93.4%, and the purity of methyl 2-amino-6-methylnicotinate was 2.5%. The yield of 2-amino-6-methylnicotinic acid ester in consideration of purity was 67.6%.

[Example 2]
4.17 g (0.025 mol) of ethoxycarbonylmethylcarboamidine hydrochloride and 3.7 ml (0.025 mol) of 1,1-dimethoxy-3-butanone were heated and stirred under reflux with 50 ml of acetonitrile. The reaction was sampled and the rate of ethyl 2-amino-6-methylnicotinate production was followed over time. The reaction yield was 63.9% 17 hours after the start of reflux.

[Example 3]
The procedure was carried out in the same manner as in Example 2 except that the amount of 1,1-dimethoxy-3-butanone charged was changed from 3.7 ml (0.025 mol) to 7.4 ml (0.05 mol). The reaction yield was 62.4% 9 hours after the start of reflux.

[Comparative Example 1]
The same procedure as in Example 2 was carried out except that ethoxycarbonylmethylcarboamidine hydrochloride (0.025 mol) was changed to ethoxycarbonylmethylcarboamidine (0.025 mol). The reaction yield 4 hours after the start of reflux was 7%. The reaction yield of Example 2 at 4 hours was 37.1%, which was lower than that of Example 2 and had more by-products.

[Comparative Example 2]
4.17 g (0.025 mol) of ethoxycarbonylmethylcarboamidine hydrochloride, 3.7 ml (0.025 mol) of 1,1-dimethoxy-3-butanone and 10.4 g (0.075 mol) of potassium carbonate 50 ml of acetonitrile The mixture was heated and stirred under reflux. The reaction yield 6 hours after the start of reflux was 16%. The reaction yield of Example 2 at 6 hours was 46.2%, which was lower than that of Example 2 and had more by-products.

[Comparative Example 3]
Acetonitrile with 4.17 g (0.025 mol) of ethoxycarbonylmethylcarboamidine hydrochloride, 3.7 ml (0.025 mol) of 1,1-dimethoxy-3-butanone and 2.7 g (0.05 mol) of sodium methoxide. It was heated and stirred under reflux with 50 ml. The reaction yield 6 hours after the start of reflux was 17%. The reaction yield of Example 2 at 6 hours was 46.2%, which was lower than that of Example 2 and had more by-products.

As shown above, the production method of the present invention is a method for producing 2-amino-6-methylnicotinic acid ester, which is an intermediate compound for producing a compound useful as an active ingredient of a drug or agrochemical, in a high yield and at low cost. Is.

Claims (2)

The following formula (1),

(In the formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, the aryl group or the alkyl group may have a substituent , and HX represents a protonic acid. )
A method for producing a protonate of 2-amino-6-methylnicotinic acid ester represented by.
In a polar organic solvent, the following formula (2),

(In the formula (2), R and HX are as defined above, and n represents an integer of 1 to 3).
When the compounds represented by the formulas (1) and (2) show basicity in at least one of the alkoxycarbonylmethylcarboamidine protonate represented by and 3-oxobutylaldehyde or its acetals. Reacted in the absence of a basic substance other than the compounds represented by the formulas (1) and (2).
The acetals are 1-methoxy-1-butanol-3-one, 1-ethoxy-1-butanol-3-one, 1,1-dimethoxy-3-butanone, 1,1-diethoxy-3-butanone, 2 , 4,4-Trimethoxy-2-butanol, 2,4,4-triethoxy-2-butanol, 1,1,3,3-tetramethoxybutane, 1,1,3,3-tetraethoxybutane, 1,1 , 3-Trimethoxy-2-butane or 1,1,3-triethoxy-2-butane, a method for producing a protonate of 2-amino-6-methylnicotinic acid ester. The following equation (1),

(In the formula (1), R represents an aryl group or an alkyl group having 1 to 8 carbon atoms, and the aryl group or the alkyl group may have a substituent.)
A method for preparing a 2-amino-6-methylnicotinic acid ester represented by the following step,
(1) In a polar organic solvent, the following formula (2),

(In formula (2), R is as defined above, n is an integer of 1-3, and HX is a protonic acid.)
The alkoxycarbonylmethylcarboamidine protonate represented by (3) and at least one of 3-oxobutyraldehyde or its acetals are reacted with the following formula (3).

(In equation (1), R and HX are as defined above.)
In the step of preparing a reaction solution containing a protonate of 2-amino-6-methylnicotinic acid ester represented by 2), when the compounds represented by the above formulas (2) and (3) are basic. The reaction is carried out in the absence of a basic substance other than the compounds represented by the formulas (2) and (3), and the acetals are 1-methoxy-1-butanol-3-one. , 1-ethoxy-1-butanol-3-one, 1,1-dimethoxy-3-butanone, 1,1-diethoxy-3-butanone, 2,4,4-trimethoxy-2-butanol, 2,4,4 -Triethoxy-2-butanol, 1,1,3,3-tetramethoxybutane, 1,1,3,3-tetraethoxybutane, 1,1,3-trimethoxy-2-butene or 1,1,3-triethoxy -2- Butane process,
(2) A concentration step of removing a polar organic solvent and a low boiling point component from the reaction solution by distillation .
(3) An extraction step of extracting the protonate of 2-amino-6-methylnicotinic acid ester represented by the above formula (3 ) from the concentrated solution obtained by the above concentration step into an aqueous layer, followed by an extraction step.
(4) A crystallization step of adding an alkaline compound to the extraction aqueous layer obtained by the above extraction step to precipitate crystals .
A method for preparing a 2-amino-6-methylnicotinic acid ester, which comprises.